Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial.

Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade ≥3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4+ and CD8+ effector T cells. T cell receptor ß-chain (TCRß) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV's mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117 .

Injury patterns and outcomes in late middle age (55-65): The intersecting comorbidity with high-risk activity - A retrospective cohort study.

BACKGROUND: Late middle age (LMA), is a watershed between youth and old age, with unique physical and social changes and declines in vitality, but a desire to remain active despite increasing comorbidity. While post-injury outcomes in the elderly are well studied, little is known regarding LMA patients. We analyzed the injured LMA population admitted to a rural, regional Level 1 Trauma Center relative to outcomes for both younger and older patients. MATERIALS AND METHODS: Our registry was queried retrospectively for patients admitted 7/2008- 12/2015; they were divided into three cohorts: 18-54, 55-65, and >65 years. Demographics, injury details, comorbidities, and outcomes were compiled and compared using ANOVA and Chi-square; p < 0.05 was significant. RESULTS: During the study period, 10,543 were admitted; 1419 (14%) were LMA who experienced overall injury mechanisms, severities and patterns that mirrored the younger cohort. However comorbidity rates were high (56.4%) and comparable to the elderly. LMA patients had the highest rates of alcohol abuse, morbid obesity, and psychiatric illness (p < 0.0001) and suffered the poorest outcomes: highest complications and hospital charges, and longest ICU and hospital LOS. LMA mortality (4.1%) was 41% higher than younger patients (2.9%; p < 0.02) and similar to the older cohort (4.7%; p = 0.32). CONCLUSIONS: The LMA population has similar mechanisms and injury patterns to younger patients, while exhibiting comorbidity rates similar to the elderly. High-energy injuries exact a greater toll in LMA with poorer outcomes and greater resource utilization. Targeted outreach for injury prevention, and future studies, are needed to address high-risk behavior, substance abuse, and societal contributors.

Impact of transfer distance and time on rural brain injury outcomes.

OBJECTIVES: After rural injury, evaluation at local hospitals with transfer to regional trauma centres may delay definitive care. This study sought to determine the impact of such delays on outcomes in patients with TBI within a mature regional trauma system. METHODS: The ETMC Level 1 Trauma registry was queried from 2008-2013 for patients with blunt TBI, aged ≥ 18 and admitted ≤ 24 hours from injury and stratified them as 'transfer' vs 'direct' admission. Demographics, transfer distance, transfer times and outcomes were compared using Chi-square, t-test and multivariable logistic regression; p < 0.05 was significant. RESULTS: During the study period, 1845 patients met inclusion criteria: 947 'direct' and 898 'transfers'. For transfers, median distance was 60.1 miles; mean time to initial care was 1.2 ± 2.7 hours and time to Level 1 care was 5.0 ± 2.4 hours. Transfer patients were older (56 vs 49 years; p < 0.01) and had more comorbidities, but had lower mean ISS (15.9 vs 18.8; p < 0.01) and lower mortality (7.0 vs 10.3%; p < 0.03), complications and LOS. Neurosurgical intervention was comparable (p = 0.88), as was mortality for patients with ISS ≥ 15 (12.4% vs 14.8%; p = 0.28). After regression analysis, advanced age and increasing ISS, not distance or time, predicted mortality. CONCLUSION: Neither transfer distance nor time independently contributed to mortality for TBI after rural injury. An established regional trauma system, with initial local stabilization using ATLS principles, may help reduce negative outcomes for injured patients in rural settings.